Autoimmune disease results from an abnormal immune response to self-antigens. At present, treatments which seek to stem the progress of human autoimmune disease are based on the general suppression of all immune responses, which can lead to long-term toxicities and suppression of protective immune responses against pathogens. There is a need for more specific therapeutic strategies to restore immune tolerance to the specific autoantigens implicated in the disease pathology.
Insulin, which is a β-cell specific major protein, is central to the disease process in Type 1 diabetes mellitus (Nakayama et al., Nature 435:220-223 (2005); Kent et al., Nature 435:224-228 (2005)). Insulin is also moderately immunogenic when used alone, and a pilot human trial suggested that it may have the effect of delaying the development of diabetes mellitus (Keller et al., Lancet 341:927-928 (1993)). Intensive insulin therapy may preserve residual beta cell functions (Shah et al., The New England Journal of Medicine 320:550-554 (1999)). However, it must be injected daily over long periods of time to induce the desired effect. Also, the use of insulin raises concerns about hypoglycemia and its sequelae.
Reintroduction of an autoantigen, such as insulin B chain, in incomplete Freund's adjuvant (IFA), has been used in animal models of diabetes, such as NOD mice (Muir et al. (1995) J. Clin. Invest. 95:628-634; Orban et al. (1999) Diabetes 48 (Supp.1):A216-A217; Ramiya et al. (1996) J. Autoimmun. 9:349-356).